The hypothalamo-pituitary-adrenocortical (HPA) axis is responsible for stress-induced glucocorticoid secretion into the systemic circulation. Glucocorticoids have multiple beneficial effects for coping with rapid changes in the environment; however, mismanagement of glucocorticoid secretion has multiple deleterious effects on the organism, and has been implicated in pathology associated with major depression, chronic stress and age-related cognitive decline. The goal of this proposal is to examine the manner in which the brain integrates the HPA stress response, focusing on the primary neurosecretory neurons in the hypothalamic paraventricular nucleus (corticotropin-releasing hormone (CRH) neurons) and their relationship to vital control elements located in limbic system sites. Initial studies (Specific Aim 1) will characterize the time course of stress-induced changes in the physiology of CRH neurons at the level of adrenocorticotrophic hormone secretagogue gene transcription, biosynthesis and secretion, and the sensitivity these changes to glucocorticoid feedback. This information will then be used to assess the influence of limbic structures (the hippocampus, amygdala and lateral septum) on stress- regulatory processes via lesion analysis (Specific Aim 2). Studies will determine whether limbic structures, which have been implicated in glucocorticoid-related HPA dysfunction, indeed exert actions on the stress response at the level of the CRH neuron. The interaction between glucocorticoid feedback and limbic actions will be investigated to determine whether effects at the CRH neuron can be associated with changes in negative feedback, or alternatively to limbic modulation of stress sensitivity. Finally, anatomical studies will define how limbic influences are conveyed to the CRH neuron, and define candidate neurochemical systems involved in HPA regulation. In combination, these experiments should provide a "blueprint" of circuits regulating CRH neuronal stress responses, and identify focal points for study of the interrelationships between HPA regulation, stress and human disease states.